Dual action of the adenovirus E1A 243R oncoprotein on the human proliferating cell nuclear antigen promoter: repression of transcriptional activationby p53

The promoter of the human proliferating cell nuclear antigen (PCNA) gene is activated by the adenovirus oncoprotein E1A 243R in HeLa cells. To underst and the effect of this oncoprotein on PCNA expression in cells that are sen sitive to oncogenic transformation by adenovirus, we studied the effect of E1A 243R on PCNA promoter-directed reporter gene expression in cloned rat e mbryo fibroblast (CREF) and primary baby rat kidney cells. In contrast to t he results obtained in HeLa cells, EIA repressed the PCNA promoter in both cell-types. Promoter analysis identified a p53-responsive element that medi ates E1A-induced repression. Repression required the intact N-terminus of E IA 243R, as shown by the ability of mutant EIA proteins to repress the prom oter, and correlated with the p300-binding region of EIA. The adenovirus E1 B 19K protein relieved repression by EIA 243R. These results reveal dual pa thways for induction of this essential DNA replication factor and suggest a mechanism for oncogenic cooperativity between the EIA and E1B oncoproteins .